Assessment of Disease Activity and Treatment Outcomes in Rheumatoid Arthritis

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which primarily causes a symmetric polyarthritis. Clinical manifestations of the disease include joint pain, stiffness, and swelling. Unless treated, this debilitating disease can progress into long-term disability. Medications for RA include synthetic disease-modifying antirheumatic drugs (DMARDs) and biologic agents. The rapid expansion of new RA drugs into the market has led to a need for health care practitioners to understand the effectiveness of each medication and the indications of use including when to initiate and stop therapies. Clinical assessment tools, including biomarkers used to indicate RA and the progression of the disease, have been proven effective for making a diagnosis and determining effective treatment regimens. Disease activity scales are also useful for guiding diagnoses and monitoring patients to assess treatment effectiveness. OBJECTIVES: To review the various clinical assessment tools that have been designed to confirm an early diagnosis of RA, measure disease progression, and assist in determining the most optimal treatment regimens for patients with RA. SUMMARY: The diagnosis of RA combines the patient history of joint pain and stiffness and the physical examination documentation of symmetric polyarticular joint swelling (synovitis). Laboratory tests including radiographs and blood tests for biomarkers can provide useful information to confirm the diagnosis of RA. Various autoantibodies have been reported in the blood of RA patients, but only the rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) have been incorporated as diagnostic measures in routine clinical practice. Monitoring and assessment instruments for RA include the Disease Activity Score 28 (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Although these clinical assessment tools have limitations, health care providers can use them as measures of disease progression and to assist in planning treatment strategies to modify disease activity and improve the quality of life for the patient.

R heumatoid arthritis (RA) is a chronic systemic inflammatory disease which primarily causes a symmetric polyarthritis, clinically manifesting joint pain, stiffness, and swelling. 1 Untreated, most patients have a progressive course resulting in short-and long-term disability. Fortunately, the number of effective medications for the treatment of RA has rapidly expanded and includes synthetic disease-modifying antirheumatic drugs (DMARDs) and biologic agents such as tumor necrosis factor inhibitors (TNF inhibitors). 2,3 It is now clear that early diagnosis, referral, and treatment of patients with RA results in improvement in clinical signs and prevention of joint destruction. 4,5 Due to the increasing number of medications for the treatment of RA, physicians and other health care providers involved in the care of RA patients must decide which medications to use, when to start them, and when to change the therapeutic regimen. In 2008, the American College of Rheumatology (ACR) published updated guidelines for the use of synthetic DMARDs and biologic agents for the management of RA. 6 The goal of treatment is not only improvement in clinical signs of inflammation, pain, and function, but also in the prevention of structural joint damage and long-term functional disability. To achieve these goals, the guidelines depend on the ability of the health care team to determine the level of disease activity and the response or lack of response that a patient may have had to a particular intervention. Accordingly, various clinical assessment tools have been validated to measure disease activity and treatment efficacy. 7 These tools can be used by health care providers to assist with clinical decisions including when to use medications, add a medication, switch medications, or even stop a medication. It is now appreciated that incorporating these clinical tools and treating to a goal can improve clinical outcomes for RA patients. 8,9 Multiple studies also have demonstrated that aggressive treatment of early RA results in better clinical outcomes than delayed therapy. 4,5 To facilitate the treatment of RA patients early in the disease course, it is essential to diagnose and refer patients efficiently. In 2010, the ACR and European League Against Rheumatism (EULAR) developed new classification criteria for RA aimed at early diagnosis. 10 While intended for use in clinical trials, physicians often use similar criteria for diagnostic guidelines. Included in these criteria are serum biomarkers that help confirm the diagnosis. In this article, we will briefly review biomarkers that assist in the diagnosis of RA. Furthermore, we will review biomarkers and clinical assessment tools of disease activity that can be incorporated into the care of the patient with RA. Together these clinical tools are important to help physicians and other health care providers patients prone to more severe disease, who might benefit from more aggressive treatment. 6 Clinical Tools for Goal-Directed Treatment Previously physician decisions for initiation and treatment modification have essentially relied on an informal assessment of disease activity and functional status of the patient. During the patient visits, physicians will often determine the number of swollen joints (SJC) and tender joints (TJC) and use this information to change therapy in the absence of clear goals. However, there are a number of limitations to using SJC and TJC as main criteria for modifying therapy, including poor reproducibility and failure to predict progressive joint damage and functional disability. 17 Fortunately, many clinical assessment tools have been developed and validated to quantify disease activity and patient functional status. 7 Multiple studies have now confirmed that goal-directed therapy in RA using quantitative measurements of disease activity results in improved clinical outcomes. 8,9 In the TICORA (Tight Control of Rheumatoid Arthritis) study, 111 patients with less than 5 years of RA disease activity were randomly assigned to an intensive management program, where treatment decisions were changed according to a target, or routine care. 8 Patients in the "tight control," or intensive group, had treatment augmented if the disease activity was higher than 2.4 using the Disease Activity Score in 28 joints (DAS28). The study examined combinations of synthetic DMARDs. The primary outcome was to decrease disease activity scores. In the end, the intensive group had lower disease activity scores and higher disease remission rates than the routine therapy group. Furthermore, patients in the intensive group had greater improvement in function and quality of life. Finally, early and more aggressive management of the disease activity in the intensive group led to slower radiographic progression and less joint damage.
The Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA) trial was a study of 299 RA patients with early RA treated (defined as symptoms less than 1 year) with methotrexate. 9 The goal was to look at remission outcomes by randomly assigning patients to an intensive, goal-directed group versus a conventional therapy group. The intensive treatment group was seen monthly with adjustment to the methotrexate dose, which was dictated by a computer program targeting a predefined quantitative response level. The conventional group was seen every 3 months with treatment adjustments driven per routine clinical care. As hypothesized, more patients in the intensive treatment group achieved remission and sustained it for a longer period of time than the conventional treatment group. Together the TICORA study and the CAMERA study support the paradigm that goal-directed treatment of RA results in improved clinical outcomes.

Assessment of Disease Activity and Treatment Outcomes in Rheumatoid Arthritis
rapidly diagnose and effectively manage RA to provide patients with markedly improved clinical outcomes.

Biomarkers Used in Diagnosis
The diagnosis is a clinical diagnosis that combines the patient history of joint pain and stiffness and the physical examination documentation of symmetric polyarticular joint swelling (synovitis). Laboratory tests including radiographs and blood tests can provide useful information that confirms or leads to the diagnosis of RA. In the past, many autoantibodies have been reported in the blood of RA patients, but only the rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) have been incorporated into routine clinical practice.
Rheumatoid Factor. Rheumatoid factor (RF) is an autoantibody (IgM, IgA, or IgG) directed against the Fc portion of IgG. RF is found in up to 75%-80% of patients with RA (seropositive RA). The specificity of the RF for RA increases with a higher serum titer, particularly in the context of a patient with an inflammatory arthritis. However, RF is not a diagnostic marker for RA. RF also occurs in other diseases including Sjögrens syndrome, cryoglobulinemia, systemic lupus erythematosus and certain infections including hepatitis C, rubella, and subacute bacterial endocarditis. Finally, RF can also be found in healthy adults as they age.
Although the titers of RF do not reliably change with disease activity, the presence of RF provides the physician with prognostic information. Seropositive RA patients and patients with high titers of RF are more likely to develop joint erosions than seronegative patients. 11 Accordingly, the most recent treatment guidelines consider the presence of RF as a marker of poor prognosis that can help guide physicians to more aggressive treatment. 6 Anti-Cyclic Citrullinated Peptide Antibodies. Anti-CCPs are autoantibodies directed against proteins that contain the amino acid citrulline. Citrulline is an amino acid formed from arginine when proteins undergo certain forms of posttranslational modification. While the sensitivity of anti-CCP for the diagnosis of RA is similar to that of RF (50%-70%, depending on the test used), it has a higher specificity than RF (95-98%). 12 Unlike RF, anti-CCPs are not commonly found in infectious diseases and do not occur with aging. 13 Anti-CCP is also uncommon in other rheumatic diseases although it can be seen in patients with palindromic rheumatism. 13,14 Similar to RF, the presence of anti-CCP at early diagnosis predicts more radiographic progression, as demonstrated by many studies showing a strong association between anti-CCP positivity and the development of bone erosions. 15,16 Furthermore, anti-CCP titers do not reliably change with disease activity. Therefore, like RF, anti-CCP can help identify cal care will likely improve treatment outcomes in RA patients.
Disease Activity Score (DAS28). DAS28 is a weight multidimensional instrument that uses a physician's assessment of the joints, the patient's overall self-assessment of disease activity, and a laboratory marker of inflammation (CRP or ESR). 20 During the examination, physicians determine the number of swollen and tender joints in 28 joints including the small joints in the hands, wrists, elbows, shoulders, and knees. The score is derived from a complicated formula, but fortunately, several online tools can easily be accessed to calculate the score. The DAS28 score can quantify disease activity at the first clinic visit and be used in subsequent visits for comparison. The scoring system has been validated for use in clinical trials as well as routine patient care. 21,22 One limitation of the DAS28 is the need to have the ESR or CRP on the day of the examination. The results of these tests may not be immediately available to the physician during the patient encounter.
Simplified Disease Activity Index (SDAI). The SDAI is another instrument that has been validated in clinical practice to assess RA disease activity. 23 The SDAI is calculated by adding up the SJC and the TJC in the same 28 joints used in the DAS28. These are added to the patient's global assessment, the physician's global assessment, and CRP. The SDAI has the advantage over the DAS28 in that the calculations are not as cumbersome, yet the performance of the SDAI is similar to the DAS28. 24 Clinical Disease Activity Index (CDAI). The CDAI is an even more simplified score than the SDAI. 24,25 The CDAI is determined by the summation of the SJC, TJC, patient's global assessment, and the physician's global assessment. 24,25 Unlike the DAS28 and the SDAI, the CDAI does not include the ESR or CRP. This enables the physician to immediately know the disease activity score and make treatment decisions during

Biomarkers for RA Disease Activity
The erythrocyte sedimentation rate (ESR) is an acute phase reactant that increases during a variety of physiological states including inflammation, and most physicians monitor ESR as a biomarker of RA disease activity. Acute phase reactants are a result of increased protein synthesis by hepatocytes or liver cells induced by inflammatory cytokines as a result of tissue injury. ESR is an indirect way of measuring for elevation in the concentration of acute phase plasma proteins, particularly fibrinogen. These acute phase proteins lead to the aggregation of erythrocytes, which causes them to descend into a test tube more rapidly. The ESR is elevated during inflammatory states such as active RA, but also from inflammation that can occur with infections or malignancies. Aberrant results in the ESR may occur during noninflammatory states where the erythrocyte morphology is altered, including anemia, older age, or a stored blood sample.
C-reactive protein (CRP) is another acute phase reactant that is increased during inflammation. CRP is present in trace concentrations in the plasma of all humans and binds to constituents of cell membranes and nuclei which are exposed at sites of tissue damage, and CRP may target the sites for clearance. Following acute inflammatory stimulus, the concentration of CRP rapidly increases for 2 or 3 days to peaks that generally reflect the extent of tissue injury, and in the absence of continuing stimulus, serum levels decrease rapidly. However, persistently elevated levels are seen in chronic inflammatory states such as active RA. Similar to the ESR, inflammation from infections and malignancies can increase the CRP; however, anemia, older age, and storage of blood samples do not significantly alter the CRP.
ESR and CRP have little use as a specific test in the diagnosis of RA, although they are part of the new ACR/EULAR Classification Criteria for RA. 10 These tests may be used to follow disease activity and monitor response to therapy. Treatment of joint inflammation in RA is usually accompanied by a decrease in the ESR and CRP. Failure to suppress the CRP is a predictor of a poor response to TNF inhibitors. 18 However, the ESR and CRP are not sufficient to determine treatment responses. Despite improvement of acute phase reactants, some patients will have progression of joint damage. 19 Therefore, the ESR and CRP should only be used in combination with other parameters by the clinician to determine disease activity.

Overview of Assessment Instruments
The development of a disease index that adequately reflects the disease activity by both subjective and objective criteria is a complicated task. Fortunately, extensive efforts have been dedicated to the development of multiple instruments that have been validated to follow disease activity in RA patients ( Table  1). The incorporation of some of these tools into routine clini-

DISCLOSURES
This supplement was sponsored by PRIME Education, Inc. and Purdue University through an independent educational grant from Genentech, Biogen Idec, and Centocor Ortho Biotech Services LLC. Kiran Farheen reports no financial or other conflicts of interest related to the subjects in this article. Sandeep Agarwal received compensation from PRIME Education, Inc. for participating in the live continuing education activity on which this article is based and for writing parts of the article. Agarwal reports payment for lectures and service on speaker bureaus from Genentech for programs on vasculitis.
the patient encounter. Similar to the SDAI, the CDAI has been reported to perform well in clinical practice. 24,25 Global Arthritis Score (GAS). The GAS uses the 28 tender joint count, modified Health Assessment Questionnaire (HAQ) score, and patient's self-reported pain. The GAS has also been shown to correlate with other measures like DAS28 and SDAI. 26 It also does not involve inflammatory markers and therefore can be readily calculated during the patient encounter.
Health Assessment Questionnaire -Disability Index (HAQ-DI). The HAQ-DI was among the first instrument based on generic, patient-centered dimensions. 27,28 It is composed of 20 items in 8 categories: dressing and grooming, hygiene, arising, reaching, eating, gripping, walking, and common daily activities. The HAQ-DI also has a visual pain scale that assesses the presence or absence of arthritis-related pain and its severity over the past week. Although not a disease activity marker, the HAQ-DI can provide important information for the physician about the patient's functional status that may not readily become apparent through the routine patient encounter.

Limitations of Disease Activity Instruments
While the literature supports that goal-directed treatments using validated instruments to assess disease activity results in improved patient outcomes, there are some limitations that should be recognized. First, the SJC and TJC in the above instruments assess only 28 joints. Notable exceptions to the joint evaluation are the feet, ankles, and hips, which are commonly affected in RA. An additional limitation to be considered are potential confounders in the patient self-reported assessments of disease activity. For example, RA patients may have concomitant osteoarthritis, fibromyalgia, or depression that could increase their self-assessment of disease activity, while not reflecting true activity of the inflammatory arthritis. Having other objective measures such as the ESR or CRP or the joint counts may help counter this potential bias. Finally, the consistency with which physicians derive their global assessments can also vary. The limitations may be overcome by using more than 1 assessment tool and educating the patient on how other diseases could impact perceptions of pain and function.

■■ Conclusions
With the growing number of medications available for the treatment of RA, physicians and patients are faced with difficult decisions pertaining to initiation and discontinuation of medications. Multiple studies support early, aggressive treatment that is goal directed. Many instruments have been validated that can be incorporated into routine clinical practice to aid in treatment decisions with the goal of optimizing clinical responses and reducing joint damage from RA.